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Companion Diagnostics: Improving Development Success and Patient Care

Interest in the development of companion diagnostics has recently surged; regulatory agencies such as the FDA have supported it and the biopharmaceutical industry has embraced it.

As our knowledge of the underlying molecular causes of cancer continues to grow, it is possible to develop personalized therapeutics that target an individual patient’s cancer, in contrast to traditional drug development that takes a “one size fits all” approach. Accompanying the development of targeted therapeutics has been an increase in development of tests that identify whether a patient’s disease expresses the molecular target, or biomarker, of a particular targeted drug. These tests are called companion diagnostics, or theranostics, and interest in their development has recently surged, furthering the promise of personalized medicine.

A frequently cited example of a successful personalized therapeutic and companion diagnostic pair is Genentech’s antibody-based drug, Herceptin® (trastuzumab), which treats patients with cancers that overexpress the HER2 receptor (such as breast cancer), and the companion diagnostic test, HercepTest. The diagnostic test was developed to select patients that will benefit from treatment with Herceptin, a blockbuster drug that had worldwide sales of $4.8 billion in 2011.

Development of companion diagnostics has been supported by regulatory agencies, such as the FDA, which recently approved GlaxoSmithKline’s Tafinlar® (dabrafenib), a BRAF inhibitor that targets a certain mutation in the BRAF gene, together with a companion diagnostic identifying patients having that specific mutation. The biopharmaceutical industry has also embraced the co-development of companion diagnostics, with companies either partnering on their development or pursuing in-house programs.

A Growing List of Advantages

Companion diagnostics confer multiple benefits to drug development because they are able to identify patients more likely to respond to a targeted drug, which in concept delivers the right drug to the right patient at the right time.

One advantage includes the increased likelihood of meeting primary endpoints, as efficacy is more likely to be demonstrated in the targeted, “biomarker positive” patient population. This approach leads to the greater probability of regulatory approval and payor reimbursement. In addition, smaller and more streamlined clinical trials in the targeted patient population may be conducted, an approach that can lead to decreased development timelines and conserved resources.

While the development of a companion diagnostic is frequently not initiated until a drug has reached later stages of development, pursuing early development of these tests, even preclinically, is also advantageous because it enables the validity of the biomarker target to be determined before significant resources have been invested, increasing the likelihood of development success.

Two examples showing the benefits of early adoption of companion diagnostics are the early FDA approvals of Roche’s Zelboraf® (vemurafenib), and Pfizer’s Xalkori® (crizotinib), both of which are targeted drugs with companion diagnostics. These therapeutics reached the market in less than five years from entering the clinic, an impressive feat that was attributed to the early adoption of the companion diagnostics. In both cases the biology of the biomarker target was well understood, which also enabled the companion diagnostic to initiate earlier in development. Also, in each case, the use of a companion test generated impressive data, with Roche’s Phase III study being halted early because of strong efficacy, and Zelboraf gaining subsequent approval based on these positive results. Pfizer’s Xalkori, along with its companion diagnostic, received conditional approval from the FDA based on data from two single-arm studies, including a Phase II trial and an expansion cohort of a Phase I study.

The early adoption of a companion diagnostic also allows certain important properties about a therapeutic target to be confirmed, including levels of its expression in specific cancers as well as its ability to functionally bind a clinical drug candidate. Each of these properties affects the safety and efficacy of the targeted drug; thus, obtaining this information early in development is useful for determining development priorities, including whether the clinical candidate will advance.

Historically, the dominant business model for developing companion diagnostics has been for a biopharma company to partner with a diagnostics firm; however, the development process may be streamlined through the use of in-house capabilities to co-develop these tests. This is especially true as early drug discovery efforts typically yield applicable information for the development of the companion diagnostic, which potentially improves success and shortens time to market.

Harnessing Imaging Technologies Holds Additional Promise

Pharma companies such as Endocyte, GlaxoSmithKline, and Pfizer are currently utilizing companion imaging diagnostics to accompany the development of targeted therapeutics. Companion imaging diagnostics hold advantages for patients, as the physical location of biomarker-positive disease, and level of biomarker expression, can quickly be visualized noninvasively and in real time. This is increasingly important in light of recent studies showing that gene expression can widely vary among different lesions, as well as across the length of an individual lesion. Expression can also dramatically change over time, which poses a challenge for the development of personalized medicines. A companion imaging diagnostic overcomes this hindrance, as it provides a comprehensive and current visual snapshot of a patient’s disease. Imaging also holds advantages over tissue biopsy, which is generally not obtained at the time of patient treatment and may not capture the patient’s current disease state as a whole.

Companion imaging diagnostics also potentially improve success rates during drug development, as the test enables the level of biomarker expression as well as the specificity of the personalized drug for that target to be investigated prior to patient treatment. Information gleaned from these analyses informs decisions involving subsequent investment of resources for development of the clinical candidate. The earlier this type of information can be obtained, the quicker important decisions regarding further clinical development can be made.

A Growing Field

Because companion diagnostics offer numerous benefits and have the strong support of multiple key stakeholders in the industry—including regulatory agencies, big pharma, biotech companies, payors, and physicians—interest in developing companion diagnostics will only grow in the future. With this surge in interest, best practices that further enhance development success will be employed, including the adoption of these tests earlier in development cycle, as well as the use of companion imaging diagnostics.

Christopher P. Leamon, Ph.D., is vice president of research at Endocyte.

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